Potential Role for AMP-Activated Protein Kinase in Hypoglycemia Sensing in the Ventromedial Hypothalamus

McCrimmon, Rory J.; Fan, Xiaoning; Ding, Yun; Zhu, Wanling; Jacob, Ralph; Sherwin, Robert S.

doi:10.2337/diabetes.53.8.1953

Cited by 138 publications

(115 citation statements)

References 44 publications

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“…In contrast to these findings, intra-VMH injection of AICAR has recently been reported to increase hepatic glucose production during a hypoglycaemic clamp, but without significant increases in plasma concentrations of glucagon and catecholamine [24]. In line with this, i.c.v.…”

Section: Discussionmentioning

confidence: 87%

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

et al. 2005

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Aims/hypothesis: Appropriate counter-regulatory hormonal responses are essential for recovery from hypoglycaemia. Although the hypothalamus is known to be involved in these responses, the molecular mechanisms have not been fully elucidated. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor, being activated during energy depletion. As AMPK is expressed in the hypothalamus, an important site of neuroendocrine regulation, the present study was undertaken to determine whether hypothalamic AMPK mediates counter-regulatory responses to hypoglycaemia. Materials and methods: Hypoglycaemia was induced by i.p. injection of regular insulin (6 U/kg) in Sprague-Dawley rats. Hypothalamic AMPK phosphorylation and activities were determined 1 h after i.p. insulin injection. To investigate the role of hypothalamic AMPK activation in mediating counter-regulatory responses, an AMPK inhibitor, compound C, was pre-administered intracerebroventricularly (i.c.v.) or dominant-negative (DN)-AMPK was overexpressed in the hypothalamus before induction of hypoglycaemia. Results: Insulin-induced hypoglycaemia increased hypothalamic AMPK phosphorylation and α2-AMPK activities in rats. The change was significant in the arcuate nucleus/ventromedial hypothalamus (ARC/VMH) and paraventricular nuclei (PVN). Prior i.c.v. administration of compound C attenuated hypoglycaemia-induced increases in plasma concentrations of corticosterone, glucagon and catecholamines, resulting in severe and prolonged hypoglycaemia. ARC/VMH DN-AMPK overexpression impaired early counter-regulation, as evidenced by reduced glucagon and catecholamine responses. In contrast, PVN DN-AMPK overexpression attenuated late counter-regulation and corticosterone responses. Conclusions/ interpretation: Systemic hypoglycaemia causes hypothalamic AMPK activation, which is important for counterregulatory hormonal responses. Our data indicate that hypothalamic AMPK acts as a fuel gauge, sensing the whole-body energy state and regulating not only energy homeostasis but also neuroendocrine functions.

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Section: Discussionmentioning

confidence: 87%

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

et al. 2005

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“…rich with leptin receptors and glucose-responsive elements analogous to those of pancreatic beta cells (Yang et al, 1999;Miki et al, 2001;Evans et al, 2004;McCrimmon et al, 2004;Squires et al, 2005). Accordingly, the VMN mediates counter-regulatory responses to hypoglycemia and energy balance responses to leptin (Jacob et al, 1997;Satoh et al, 1997;Choi et al, 1999;Dube et al, 1999;Elias et al, 2000;Borg et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

Fekete

Inoue

Zhao

et al. 2006

Neuropsychopharmacol

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Brain corticotropin-releasing factor/urocortin (CRF/Ucn) systems are hypothesized to control feeding, with central administration of 'type 2' urocortins producing delayed anorexia. The present study sought to identify the receptor subtype, brain site, and behavioral mode of action through which Ucn 3 reduces nocturnal food intake in rats. Non-food-deprived male Wistar rats (n ¼ 176) were administered Ucn 3 into the lateral (LV) or fourth ventricle, or into the ventromedial or paraventricular nuclei of the hypothalamus (VMN, PVN) or the medial amygdala (MeA), regions in which Ucn 3 is expressed in proximity to CRF 2 receptors. LV Ucn 3 suppressed ingestion during the third-fourth post-injection hours. LV Ucn 3 anorexia was reversed by cotreatment with astressin 2 -B, a selective CRF 2 antagonist and not observed following equimole subcutaneous or fourth ventricle administration. Bilateral intra-VMN and intra-PVN infusion, more potently than LV infusion, reduced the quantity (57-73%) and duration of ingestion (32-68%) during the third-fourth post-infusion hours. LV, intra-PVN and intra-VMN infusion of Ucn 3 slowed the eating rate and reduced intake by prolonging the post-meal interval. Intra-VMN Ucn 3 reduced feeding bout size, and intra-PVN Ucn 3 reduced the regularity of eating from pellet to pellet. Ucn 3 effects were behaviorally specific, because minimal effective anorectic Ucn 3 doses did not alter drinking rate or promote a conditioned taste aversion, and site-specific, because intra-MeA Ucn 3 produced a nibbling pattern of more, but smaller meals without altering total intake. The results implicate the VMN and PVN of the hypothalamus as sites for Ucn 3-CRF 2 control of food intake.

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“…There is also widespread agreement that treatments which activate AMPK in the hypothalamus, such as infusion with the nucleoside 5-aminoimidazole-4-carboxamide riboside, treatment with the gut hormone ghrelin or cannabinoids, or hypoglycaemia, all increase food intake in rodents (30)(31)(32) .…”

Section: Regulation Of Amp-activated Protein Kinase By Adipokines Andmentioning

confidence: 99%

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Hardie

2010

Proc. Nutr. Soc.

118

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The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP :ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-ofrapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished. Muscle: Exercise: Type 2 diabetes: NutraceuticalsAnimal cells take up fuel molecules such as glucose or fatty acids, and oxidise them to CO 2 via the process of catabolism. Much of the energy released during this process is used to convert ADP to ATP, which can be likened to the chemicals in a rechargeable battery. Extending this analogy, catabolism charges up the battery by converting ADP to ATP, whereas most other cellular activities (e.g. growth, division, secretion and movement) require energy and are driven by the conversion of ATP back to ADP, thus draining the battery. Just as machines that utilise rechargeable batteries (such as laptop computers or electric cars) require systems to monitor the state of the battery, cells require systems to monitor their ATP : ADP ratio and match the rates of uptake and consumption of carbon nutrients to the rate of ATP utilisation. The topic of this review is the AMP-activated protein kinase (AMPK), which is the major system responsible for achieving this task in eukaryotes. Researchers who wish to understand disorders of energy balance, such as obesity and type-2 diabetes, have been particularly interested in the system. Protein kinases, including AMPK, are signalling enzymes that modify the function of target proteins by transferring phosphate groups from ATP to side chains of specific amino acids, usually serine o...

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Potential Role for AMP-Activated Protein Kinase in Hypoglycemia Sensing in the Ventromedial Hypothalamus

Cited by 138 publications

References 44 publications

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

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